The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of Kras. However, expression of mutant Kras alone is not sufficient to drive pancreatic ductal adenocarcinoma (PDAC) in adult mice. Obesity is a metabolic disorder and is a risk factor for PDAC. One of the main factors that contributes to the development of obesity is high-fat consumption. Recent studies have demonstrated that High-Fat-Diet (HFD) can promote oncogenic Kras mediated development of pancreatic intraepithelial neoplasia and PDAC. However, it is not clear why mice with oncogenic KrasG12D expression are predisposed to HFD mediated pancreatic carcinogenesis. Here, we report that Ras activity dramatically reduces the expression of fibroblast growth factor 21 (FGF21). FGF21 is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 lower serum free fatty acids and lead to weight loss in obese mice. FGF21 is highly expressed in pancreatic acinar cells and is a potential autocrine factor. High levels expression of FGFR1 and β-Klotho, key components for specific sites of FGF21 action, were observed on normal control mouse pancreatic acinar cells using both qRT-PCR and immunohistochemistry technics. FGF21 levels were dramatically reduced (∼6-fold) by Cre-mediated knock-in of oncogenic KrasG12D within one week and further decreased by more than 100-fold within 7 months. This effect of KrasG12D may have been mediated by decreased expression of pancreatic transcription factor Mist1, which was also observed. To dissect obesity and oncogenic KrasG12D mediated PDAC, we fed adult KrasG12D expressing mice with HFD or HFD+FGF21. We observed that KrasG12D expressing mice fed with HFD+FGF21 for 9 weeks significantly lower body weight and pancreatic triglyceride, as well as dramatically fewer PanIN lesions and tumor, compared with KrasG12D mice on a HFD without FGF21. FGF21 treatment extended survival of KrasG12D expressing mice on a HFD. Our results suggest that pancreas-derived FGF21 is an important metabolic regulator which is silenced by oncogenic KrasG12D expression and plays an important role in preventing HFD induced PDAC in KrasG12D expressing mice.

Citation Format: Weiqin Lu, Yaying Yang, Xiaojie Wang, Yan Liu, Yongde Luo, Robert A. Wolff, James L. Abbruzzese, Craig D. Logsdon. FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 891. doi:10.1158/1538-7445.AM2015-891

©2015 American Association for Cancer Research.
2015